1,721,003 research outputs found
The Role of the Bone Marrow Immune Niche in Preventing Relapse in Adult B-ALL Following Reduced Intensity Conditioning Allogeneic-HSCT
Get PDFReduced intensity-conditioning (RIC) allogeneic haematopoietic stem cell transplants (alloHSCT) improved event-free survival for patients > 40 years old, as established by the UKALL14 (NCT01085617) trial for patients with B-cell acute lymphoblastic leukaemia (B-ALL). Persistence or reappearance of minimal residual disease is a strong predictor of relapse after RIC alloHSCT in ALL and is associated with ineffective graft-versus-leukaemia (GVL) responses by donor T cells. In this thesis, I sought to characterise differences in the bone marrow (BM) immune cell composition from adult patients with B-ALL who underwent RIC alloHSCT with or without subsequent relapse.
I first identified using mass cytometry, and confirmed using single RNA-sequencing (scRNA-seq), an enrichment in early CD4+ T cell subsets in the BM T cell compartments of patients in remission who later relapsed (CR→Rel) compared to patients who remained in long term remission (CR→CR), post-alloHSCT. However, low sample sizes meant that conclusions lacked statistical power. Furthermore, I also identified an inflammatory myeloid signature using bulk RNA-sequencing, which was further characterised in scRNA-seq in patients who later relapsed, which potentially represented a functional pro-inflammatory immature neutrophil population. Cell-cell interactome analysis predicted increased pro-inflammatory signalling pathways in CR→Rel compared to CR→CR, further suggesting a chronically inflamed BM prior to relapse post-alloHSCT. Investigation of the BM at B-ALL diagnosis identified a similar myeloid signature in patients who eventually relapsed. Further interrogation of this signature in a 150-patient UKALL14 validation cohort identified a significant correlation of the myeloid signature with EFS at diagnosis, however this was not an independent predictor of outcome when adjusted for age.
In summary, my thesis identified BM immune signatures potentially associated with future relapse after RIC alloHSCT for B-ALL, and my data may suggest that a myeloid signature is enriched in both the diagnostic and post-alloHSCT samples of patients destined to relapse, which could be supported by its correlation with age and EFS in a large diagnostic cohort
The effect of the bone marrow microenvironment in B acute lymphoblastic leukaemia upon anti-leukaemia T cells
No full textDeveloping models of T cell mediated injury to the bone marrow niche
Get PDFHaematopoiesis takes place within a tightly regulated niche, which provides the microanatomical, metabolic and immunological context for normal haematopoietic function. Several diseases characterised by bone marrow failure are mediated by T cell mediated inflammation within the bone marrow niche. These include poor graft function following allogeneic stem cell transplantation (alloSCT), immune effector cell-associated haematotoxicity following chimeric antigen receptor T cell therapy and immune aplastic anaemia. A mechanistic understanding of the cause of bone marrow failure in these conditions is required to facilitate the rational development of new interventions to improve patient outcomes. These mechanistic insights are impeded by limitations in existing pre-clinical models, which calls for the development of novel tractable model systems. Bone marrow stromal populations are a target for graft-vs-host disease (GVHD) following alloSCT with implications for both stromal and haematopoietic function. We hypothesise that the injury to bone marrow stromal populations by alloreactive T cells can be used as the basis for new models to explore the impact of T cell mediated injury to the haematopoietic niche. The work presented in this thesis is nested within a larger project with the following aim: To develop and mechanistically interrogate tractable models of T cell mediated injury to the haematopoietic niche, to identify novel targets for the treatment of cytopenias following cellular therapies, and related conditions. The scope of the work presented in this thesis is the initial development of these model systems; a murine model of GVHD optimised to study the impact of GVHD on the haematopoietic niche, and an in vitro system using human iPSC-derived bone marrow organoids. Prior studies exploring the impact of GVHD on haematopoiesis in mice used models characterised by severe systemic illness and short survival, which limits the study of engrafting haematopoiesis. This limitation was circumvented by selecting a transplant model characterised by a mild GVHD phenotype and carefully titrating the dose of graft T cells. This resulted in a phenotype in the GVHD cohort relative to controls characterised by anaemia, changes to bone marrow stromal population architecture and a trend towards a reduction in CD201+ long-term haematopoietic stem cells. Bone marrow failure and pancytopenia were not observed in these experiments, but these results will guide ongoing model development. A recently published protocol to generate human iPSC-derived bone marrow organoids was established within our laboratory. This will form the basis of an experimental system reacting primary donor T cells against organoids to explore T cell mediated injury to the bone marrow niche in a novel model system using human tissue. An attempt was also made to generate an MHC class I/II K/O iPSC line, to generate hypo-immune organoids for use as a negative control within this experimental system
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A yeast model of Bloom's syndrome
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Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia
No full textAcute myeloid leukaemia (AML) is an aggressive blood cancer that can be treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Although allo-HSCT reduces the chance of relapse because of the Graft-versus-leukaemia (GvL) effect, it is also associated with the Graft-versus-Host Disease (GvHD). This and other treatment or disease related complications mean that only around half of transplanted AML patients survive at 3-years[1]. To harness the GvL effect, on-going research is trying to identify novel GvL-specific allogeneic peptide antigens presented by the major histocompatability complex (MHC), called minor histocompatability antigens (miHA). However, it remains unclear which miHAs mediate a successful GvL effect and what GvL-specific T cell functions are associated with it. This work describes a novel HLA-DP-restricted PADI4 miHA response identified as part of a previous allogeneic antigen screen in a cohort of AML patients with long-term remission post-transplant. Antigen-specific allogeneic T cells were successfully isolated and their T cell receptor (TCR) transferred to third-party primary T cells. PADI4 TCR T cell activation was seen to cancer cell lines, where it could also exert a growth inhibitory effect. Although this work did not show evidence of direct T cell activation to primary leukaemia samples, leukaemia-derived antigen was successfully presented by primary monocyte-derived dendritic cells. PADI4 miHA expression is haematopoietically restricted, suggesting no reactivity to the GvHD target tissues. However, PADI4 TCR T cell activation, without target cell killing, was seen to healthy monocytes. Overall, this data supports the idea that the PADI4 miHA response could exert an anti-leukaemic or a broader anti-haematopoietic effect. This work provides an important starting point to further investigate the PADI4 TCR for its anti-leukaemic effect and the importance of the PADI4 miHA response in other AML patients. It also highlights the role of CD4+ MHC class II-restricted T cell responses in GvL
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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